4-sulfonyl derivatives of salicylic acid



United States Patent 25852357 4 SUISFGNYL DERIVATIVEOF SAEICYLIC ACID Ernst-Schraufstatter, Wuppertal-Elberfeld, }errnany,1 -as- ..s ignor..to..Schenleylndustries, Inc.,. New .York, N. Y.,

'a' corporation of-D'elaware No :Drawing. '*Application April' 5,1955

?Serial-No.f499,527

Claims priority, application Germany April 9,1954

6 Claims. (Cl.=-26(l519) This invention relates to novel 4=sulfonyl derivatives of salicylic acid.

It is known that the addition ofa sulfur group to salicylic acid proceeds with thes'ubstitution eifected at the 5 position. Thus, for "example, in the sulfochlorination of salicylic acid, salicylic acid S-sulfochloride is exclusively produced.

One object of this invention is a processv for the-sulifochlorination of salicylic acid'which 'all'o'ws thelproduc- 'tion ofsalic'ylieacid 4-'sulfoch1oride i'ngo'odiyield.

A furthefobje'ct of this invention is"the"p'roduction of novel"salicylic acid 4=sulfonamides 'which'have been f oundfio constitute valuble pharmaceutical products- "Thesean'd still furtherobjects'will become apparenffrom the following' description:

In accordance with the invention 4-aminosalicylic acid is diazotized and reacted with a solution of hydrogen chloride and sulfur dioxide in water and/ or organic solvents such as glacial acetic acid, which contain catalytic amounts of a copper salt. The diazotation can be effected prior to the reaction with the hydrogen chloride-sulfur dioxide solution or may be efiected in the solution of hydrogen chloride and sulfurdioxide.

The diazotation of the 4-amino salicylic acid is elfected inthepresenceof hydrochloric:acidandipreferably in the .presence of a water-miscible. organic-acid. such. as acetic acid. TEquimolecular amountsof an alkali metal nitrite ,oran alcohol nitrite or nitrous acid anhydride should also be, present.

' The concentration of a hydrochloric acid should. be as "high as'possible'. Amounts of hydrochloric acidofat least2 arid'up't'o I 'timesthe equivalent amount of the t-amino salicylic acid shouldfbe used. Thefldiazotation may be enacted at'temperature's between about f'20 and 10C.

The. r'eactionof 'the diazonium chloride 'withthe. sulfur dioxide may beeifec't'edat temperatures.'betweeniabout "20"C. and +'50"C., and mayQfor example, be efiec'ted -insulfurdioxide in the'absence of water. If, however, anaqueous-solutionis employed, the same should be rendered strongly acid with hydrochloric acid. The solid 'diafionium chloride 'or zinc chloride double salt may be contacted with liquid sulfur dioxide in an organic solvent such as acetone, dioxane or glacial acetic acid. A1- ternatively, the'diazoniumchlorideinthe form of a concentrated hydrochloric acid solutionor suspension may be contacted with-a solution of sulfur-dioxide'in a-watermiscible, organic acid, such as acetic acid or gaseous sulfur dioxide, may be introduced into the solution or suspension of ithe diazonium;-'chloride, preferably with the additionrof awate'r-miscible organicacidsuchas .acetic acid. The contacting. should. preferably be effected inatherpres- .e'nce of a coppercatalyst. Coppenpowder isprefer'able as .thec'at'alyst,:although a copper salt soluble in the reaction 'm'mturemay be used in amounts -of from 0.1 to based on the amount of the diaz'onium chloride. Without the use of a catalyst, the reaction proceeds more Patented Sept. -16, .1958

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2 The reaction elfects an 'exchange of the 4-amino group for the sulfochloride radical; resulting in the formation of salicylic acid 4-sulfochloride.

It has further been found that, if the salicylic acid 4- 5 sulfochloride thus obtainedis' reacted with ammonia or amines novel salicylic acid4-sulfonamides are obtained which constitute valuableipharmaceutical products.

The reaction of the salicylic .acid 4- sulfochloride with ammonia or an amine proceeds. inzthe, conventionalmanner. -An excess of ammoniaor anagent-yielding ammonia such as ammonium carbonate may be used. T'When using an amine as the' reactanttheuse of anexcessis also-advisable. If 'equi'mol'e'cular propoftions. of ammonia or amine are employed an acid binding agentflikesodium 'bica'rbonate, sodiumcarboiiate -or alkali metal hydroxide should be present. The reaction may be carried out "in an aqueous medium or in an organic solvent, like benzene, ethanol, dioxane etc. or in a mixture of organic solvents. Temperatures of between 0 and 100 C. are applicable, room temperature being preferred.

The salicylic acid 4-sulfonamides produced in accordance with the invention haveithe general formula:

l-JSOr-X :in which. X :may be 1 a NH i'r'adicaL- :a =.NR radical .iwherein R-is a' lowersaliphaticuliydrocarbon radical :such

as a methyl or propyl radicalon a l l radical Furthermore, the new compounds in accordance with the invention may be in the form: of an N,N'-bisphenylene di- 40 amine, wherein X in the general formula will represent a N-SOrG-C 0 on radical These novel salicylic acid 4=sulfonamides have an extremely high antipyretic andzan'tiarthritic activity. They may be subsequently acylated at the hydroxy group or estcrified at the carboxy group in accordance with conventional methods.

The following examples are given by way of illustration and not limitation:

,Three hundred grams of :sodium ,p-amino-salicylate (.2 H5O) are dissolved in 480 ml. of aterandZOnil. of

t a '10 .percent sodium hydroxide. solution. and. added .to. a solution of lll'i-grams of sodiumnitrite 'inTZI Oi m1- of wa- 60 ter. .Thesolution obtained .is slowly added withfstrong stirring at I0" CJ-to 45'0 nil. of,,.glac'ialaceticacid and 900 ml. of hydrochloric acid. In the meantime750 ml.

of glacial acetic acid are saturated with sulfur dioxide and 3 8090 percent, melting at 190-19l C. with decomposition, and having the formula:

G OH Example 2 S 0 :NH: Example 3 15.3 grams of salicylic acid 4-sulfochloride are added 7 with stirring into a mixture of 20 grams of di-n-propylamine and ml. of benzene. After stirring for one hour petroleum ether is added to the solution, the residue is suction filtered and treated with dilute hydrochloric acid. The salicylic acid 4-sulfonyl-di-n-propylamide obtained is recrystallized from 50 percent alcohol and melts at 147 C. It has the formula:

In the same manner salicylic acid 4-sulfonyl-di-nbutylamide of the melting point 135 C. can be obtained when di-n-butyl-amine is used instead of di-n-propylamine. It has the formula:

BO:N(C4 n)s Example 4 noocGsomvn on and can be recrystallized from 50 percent alcohol. It melts at 283 C. This compound may be designated N,N' bis (3-hydroxy 4 carboxy phenylsulfonyl)-mphenylene diamine.

4 The N,N-bis-(.3-hydroxy-4-carboxyphenylsulfonyl)-pphenylene diamine of the melting point 315 C. is formed by using p-phenylene diamine instead of m-phenylene diamine.

Example 5 Twenty-three and six-tenths grams of salicylic acid 4- sulfochloride are dissolved in 75 ml. of ethanol and 28 ml. of aniline are added with cooling. After standing for some time the reaction mixture is diluted with water and acidified with hydrochloric acid. After recrystallizing from 50 percent alcohol the salicylic acid 4-sulfonic acid anilide obtained melts at 246 C., and has the formula:

O O OH Example 6 Twenty-three and six-tenths grams of salicylic acid 4- sulfochloride are added with stirring and cooling to 50 ml. of a 30 percent dimethyl amine solution. After some hours the reaction mixture is acidified with dilute hydrochloric acid, the residue is separated and recrystallized from 25 percent acetic acid. The salicylic acid 4-sulfonyl-dirnethylamide obtained melts at 220 C. and has the formula:

In order to illustrate the pharmaceutical characteristics of the new salicylic acid 4-sulfonamide and to compare the same with the known salicylic acid 5-sulfonarnide, the efiect of these two compounds, an experimental protein arthritis of rats was examined. A number of experi mental animals were given intraperitoneal injections and were administered doses of compounds per 0s. The amount that the swellings were reduced in the treated animals was compared with the size of the swelling in the untreated control animals. The results are shown in the following table wherein the percent figures indicate the percentage of swelling remaining after the treatment as compared with a 100% swelling of the control animals.

Salicylic acid 4-sul- Salicylic acid 5-sulfonamide tonamide Dose per rat lntrapertper os, intraperlper os,

toneal, percent toneal, percent percent percent 41 toxic 100 100 83 99 100 100 As may be seen, an appreciable reduction in the swelling occurs with the use of salicylic acid 4-sulfonamide, whereas there is at best an imperceptible effect from the administrations of the salicylic acid S-sulfonamide. The arthritis may thus be beneficially influenced by the 4- sulfonamide, while the S-sulfonamide does not show any such beneficial efiect.

I claim:

1. A salicylic acid 4-sulfonamide selected from the 5 6 group of salicylic acid 4-sulfonamides having the general sulfonyl-dialkylamide selected from the group consisting formula: of salicylic acid 4-sulfonyl-di-n-propylamide, salicylic acid 4-sulfonyl-di-n-butylamide, and salicylic acid 4-sulfonyl-di-methylamide.

5 4. As a new chemical compound salicylic acid 4- 0E sulfonic acid anilide.

5. As a new chemical compound a phenylene diamine v selected from the gnoup consisting of N,N'1bis-(3-hy- 0 x droxy-4-ca1'boxyphenylsulfonyl) m phenylene diamine in which X is a member selected from the group consistand 'bls'(3'hydroxy 4 carboxyphenylsulfonyn'p' phenylene diamine. mg of NR2 and 6. As a new chemical compound salicylic acid 4-sulfochloride.

OH O I References Cited in the file of this patent 0 UNITED STATES PATENTS and R is a member selected from th group i ti f 2,233,296 Nelles e a1 25, 9 1 lower ahphatic hydrocarbon radicals and a FOREIGN PATENTS 22,854 Great Britain June 11, 1914 C radical OTHER REFERENCES foil $3: new chemical compound salicyllc acid 4-sul- Rodd: Chemistry f C b n Compounds, 111A, PP-

3. As a new chemical compound a salicylic acid 4- 258-261 and 296 (1954) 

1. A SALICYLIC ACID 4-SULFONAMIDE SELECTED FROM THE GROUP OF SALICYLIC ACID 4-SULFONAMIDES HAVING THE GENERAL FORMULA: 